Monoglycerides 0f (carbgxy pl-ienyl
amtno) chlgroqukngltnes



United States Patent 3,232,944 MONOGLYCERIDES 0F (CARBGXY PHENYL AMTNO)CHLGROQUENGLTNES Andr Allais, Paris, and Jean Meier, Coeniily-hampigny,Seine, France, assignors to Ronssel-Uclaf, S.A., Paris, France, acorporation of France No Drawing. Filed July 31, 1963, Ser. No. 299,050Claims priority, application France, Aug. 20, 1962, 907,282.; Nov. 20,1962, 916,016 8 (Iiaims. (Cl. 260-286) The invention relates to thenovel product, the u-monoglyceride of 4-(2-carboxyphenylamino)-7chloroquinoline having the formula and its non-toxic, pharmaceuticallyacceptable acid addition salts. The invention also relates to a novelmethod of preparing the said wmonoglyceride and to novel intermediatesformed therein.

In commonly assigned, copending application Serial No. 207,388, filedJuly 3, 1962, now Patent No. 3,174,972, there are described quinolinederivatives such as 4-(2'- carbomethoxyphenylamino)7-chloro-quinolineand 4-(2'- carbobutoxyphenylamino)-7-chloro-quinoline which possess ananti-inflammatory and analgesic activity. However, the wmonoglyceride of4-(2-carboxyphenylarnino)- 7-chloro-quinoline of the present inventionpossesses a remarkable anti-inflammatory and a more intense and moreregular analgesic activity.

It is an object of the invention to provide the novel product, thewmonoglyceride of 4 (2 carboxyphenylamino)-7-chloro-quinoline and itsacid addition salts.

It is another object of the invention to provide a novel process for thepreparation of the e-monoglyceride of4-(2'-carboxyphenylamino)-7-chloro-quinoline.

it is a further object of the invention toprovide novel intermediatesfor the a-monoglyceride of 4-(2-carboxyphenylarnino)-7-chloro-quinoline.

It is another object of the invention to provide a novel method ofrelieving pain and inflammatory manifestations.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

The novel quinoline derivatives of the invention are selected from thegroup consisting of the a-monoglyceride of 4 (2-carboxyphenylamino) 7chloro-qninoline having the formula 3,232,944 Patented Feb. 1, 1966drogenating the latter to form (2,3-isopropylidenedioxy)-propyl-anthranilatc, condensing the latter with 4,7-dichloro-quinolinein the presence of a mineral acid to form the corresponding mineral acidsalt of the a-monoglyceride of 4(2-carboxyphenylamino)-7chloro-quinoline and reacting the latter with an alkaline agent to formthe a-monoglyceride of 4-(2'-carboxyphenylamino)-7-chloroquinoline whichmay be reacted with an organic or mineral acid to form the desired acidaddition salt.

A preferred mode of the process comprises reacting onitrobenzoylchloride with 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane in. thepresence of pyridine, to form (2, S-isopropylidenedioxy)-propyl-onitrobenzoate, catalytically hydrogenating the latter in ethanol in thepresence of a palladized carbon black catalyst to form(2,3-isopropylidenedioxy) propyl anthranilate, condensing the latterwith 4,7-dichloro-quinoline in the presence of hydrochloric acid to formthe hydrochloride of the tit-monoglyceride of4-(2-carboxyphenylamino)-7-chloro-quinoline, reacting the latter with anammonia solution to form the a-monoglyceride of4-(2'-carboxyphenylamino)- 7-chloro-quinoline. The reaction scheme isillustrated in Table I.

The novel analgesic and anti-inflammatory compositions of the inventionare comprised of a compound selected fromthe roup consisting of theot-monoglyceride of 4-(2'-carboxyphenylamino)-7-chloro-quinoline and itsnon-toxic pharmacologically acceptable acid. addition salts and a majoramount of a pharmacological carrier. The compositions can be used forthe treatment of muscular, articular or nervous pains, rheumaticdisturbances, toothaches, zona, migraines and febrile and infectiousstates.

The compositions may be in the form of injectable solutions, ofinjectable suspensions, prepared in ampules, in multiple-dose fiacons,of tablets, of sugar-coated tablets, of syrups, of suppositories and ofpomades.

The novel method of relieving pain and inflammatory manifestationscomprises administering an effective amount of a compound selected fromthe group consisting of the a-monoglyceride of4-(2'-carboxyphenylamino)- 7-chloro-quinoline and its non-toxic,pharmacologically acceptable acid addition salts. The usual dosage is0.100 to 0.200 gm. per individual dose and 0.200 to 0.500 gm. per day inthe adult depending upon the method of administration. The saidquinolines may be administered orally, transcutaneously, topically onthe skin and mucous membranes or rectally.

In the following example there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE Preparation of the a-manoglyceride of 4-(2-carb0xyphenylamino)-7-chl0r0-quin line Step A: Preparation of(2,3-is0pr0pylidenedi0xy)-pr0- pyl 0-nitr0benz0ate.59.6 gm. of 2,2dimethyl 4 hydroxymethyl-1,3-dioxolane were dissolved under agitation in60 cc. of anhydrous pyridine. The solution was cooled to C. and 86.5 gm.of o-nitrobenzcyl chloride (prepared by Lockermann et al., Ber., vol.80, p. 488, 1947) were slowly introduced into it. The reaction mixturewas agitated for a period of two hours at room temperature and then waspoured into 500 cc. of ether. The mixture was filtered and the filtratewas washed successively with 0.5 N sulfuric acid solution, with aqueoussodium bicarbonate solution and finally with water until the wash waterswere neutral. The washed solution was dried over sodium sulfate andfiltered again. The filtrate was distilled to dryness under vacuum toobtain 116.5 gm. (being a yield of 92%) of(2,3-isopropylidenedioxy)-propyl o-nitrobenzoate in the form of a yellowoil which distilled at 178180 C. at a pressure of 1 mm.

Analysis. C H O N, molecular weight=281.26. Calculated: C, 55.51%; H,5.38%; N, 4.98%. Found: C, 55.8%; H, 5.4%; N, 5.0%.

This compound is not described in the literature.

Step B: Preparation of (2,3-isopropylidenedioxy)-pr0pyl anthranilate.80gm. of (2,3-isopropylidenedioxy)-propyl o-nitrobenzoate, obtained asdescribed in Step A, were subjected to hydrogenation for a period of onehour in 800 cc. of absolute alcohol in the presence of 2 gm. ofpalladized carbon black as catalyst. The reaction mixture was filteredand the filtrate was evaporated under vacuum to obtain 70.5 gm. (being ayield of 98.5%) of (2,3-isopropylidenedioxy)-propyl anthranilate in theform of a yellow oil which distilled at 159-160 C. under 0.5 mm. ofpressure.

Analysis. C H O N, molecular weight=251.28. Calculated: C, 62.13%; H,6.82%; N, 5.58%. Found: C, 62.1%; H, 6.9%; N, 5.6%.

This compound is not described in the literature.

Step C: Preparation of the a-monoglyceride of 4-(2'- and the salt wastaken up in 600 cc. methanol at reflux. The solution was made alkalineby the addition of 120 cc. of amonia solution and iced for a period ofone hour. The crystalline precipitate obtained was vacuum filtered,washed with water and dried to obtain 38.5 gm. (being a yield of 56%) ofthe a-monoglyceride of 4-(2-carboxyphenylamino)-7-chloro-quinolinehaving a melting point of 165 C.

The product occured in the form of pale yellow prisms and was insolublein water, ether, benzene diluted alcohols, olive oil and chloroform,slightly soluble in absolute alcohol, dioxane, tetrahydrofuran andacetone, and soluble in dilute aqueous acids and alkalis.

Analysis. C19H17O4N2C1, molecular weight=372.8. Calculated: C, 61.21%;H, 4.59%; N, 7.51%; Cl, 9.51%. Found: C, 61.5%; H, 4.5%; N, 7.3%; Cl,9.6%.

This compound is not described in the literature.

PHARMACOLOGICAL STUDY Analgesic activity The test employed was based onthe fact noted by Koster et a1. (Fed. Proc., 1959, 18, 412) according towhich the introperitoneal injection of acetic acid provoked repeatedcharacteristic movements of stretching and twisting persisting in micefor more than six hours. Analgesics prevent or suppress this syndromewhich is an exterior manifestation of a diffuse abdominal pain.

A solution of 6 parts per thousand of acetic acid in water containing10% of arabic gum was employed and the dose releasing the syndrome inmice under these conditions was 0.01 cc./gm., being 60 m g/kg. of aceticacid. The analgesics were administered orally to groups of five mice,which had not been fed for 24 hours, a half hour before theintra-peritoneal injection of the acetic acid. The stretchings wereobserved, noted and counted for each mouse and then additionally bygroups of five, during a period of observation of fifteen minutesimmediately after the injection of acetic acid. The average number ofstretchings observed on the twelve control groups of five mice duringthe period of observation indicated, was established at 505 per group.

The product of the invention which was administered in the form of anaqueous suspension containing polysorbate diminished the number ofstretchings in a fashion obviously proportional to the doses utilized,as is shown in Table II which compares4-(2'-carbomethoxyphenylarnino)-7-chloro-quin0line and aspirin with thesaid a-monoglyceride.

C ontrols:

Group No. 1 Group N o. 2. Group No. 3.. Average The a-monoglyceride of4-(2-carboxyphenylamino)-7-chloroquinoline. 4-(2-carbomethoxy-phen- 20ylamino)-7-chloro- 50 quinoline. 100

50 Aspirin 100 carboxyphenylamino)-7-chl0r0-quinoline.-A mixture of 48gm. of (2,3-isopropylidenedioxy)-propyl anthranilate, 36 gm. of4-,7-dichloro-quinoline, 36 cc. of concentrated hydrochloric acid and300 cc. of water was agitated while heating to reflux for a period oftwo hours. The reaction mixture was filtered and the filtrate wasallowed to stand at a temperature of 0 C. for a period of threeAnti-inflammatory activity (A) Test 0 the edematized paw in the rat.Thetest hours. The hydrochloride salt was then Vacuum filtered 75 consistedin administering to rats Weighing from to 170 gm. in a single injection500 'y of naphthoylheparamine in the aponeurotic pad of a posterior pawin order to provoke the formation of an inflammatory edema. The productsto be studied were administered orally one hour before the injection.The maximum circumference of the two posterior paws was measured threehours after the injection and the difference between the circumferencesof the two posterior paws of each animal (paw having received theinjection of naphthoylheparamine and the intact paw) served to evaluatethe extent of the inflammation. The measure of the inflammation in thetreated rats was expressed in percentage with reference to those of thecontrol animals.

The following results were obtained:

With aspirin: The average eflicacious dose DE was 100 mg./kg.

With amodiaquinine: The average efl'icacious dose DE was greater than200 mg./ kg.

With the ot-monoglyceride of4-(2-carboxyphenylamino)-7-chloro-quinoline: A dose of SO mg./kg.brought about a diminution of the percentage of edema of 48% and a doseof 100 mg./kg. brought about a diminution of the percentage of edema of62%. The average efiicacious dose DE is thus about 60 mg./kg.

Acute toxicity on mice by oral administration The products to be testedwere utilized in aqueous suspensions containing polysorbate 80 and wereeach administered orally with the aid of a gastric tube at doses of 1and 2 gm./ kg. to two groups of ten mice which had been starved from theday before. The animals were held under observation for a period ofeight days and the phenomena of intoxication or the mortality was notedeach day. The animals exhibited a depressive state for several momentsafter the injection. At a dose of 1 gm./kg., a mortality of threeanimals was: observed and at a dose of 2 gm./kg., a mortality of fouranimals out of ten was observed. The LD is thus greater than 2 gm./kg.,while the LD for aspirin is 1.5 gin/kg. under the same conditions.

A second test was run to compare the toxicity of the amonoglyceride of4-(2-carboxyphenylamino)-7-chloroquinoline with that of4-(2'-carbomethoxyphenylamino)- 7-chloro-quinoline. The compounds wereadministered orally in suspensions to groups of rats at dosages of 1 and2 gm./ kg. every day except Sunday, i.e., 12 times in fourteen days andthe mortality and frequency of intestinal ulcers was determined. Theresults are summarized in Table IV.

TABLE IV Mortality Intestinal Ulcers Doses in Number Compoundadministered rug/kg. of rats Absolute Percent Frequency Percent valueControls with dispersant 0 0 0 0 4-(2'-carbomethpxyphenylamino)-7- 100 81 12 0 0 ChlOI'O CllllllOllllG. 200 16 3 19 6/15 40 The u-monoglycerideo1 4-(2-carboxy- 100 8 0 0 0 0 phenylamino)-7-ch1oro-qui n0line. 200 8 00 1 12 (B) Test of erythema by ultraviolet rays-This test consisted inexposing a lot of guinea pigs whose dorsal skin was previously shaved toirradiation by means of a lamp generating ultraviolet rays for a periodof two minutes at a distance of 20 cm. The erythema provoked wasevaluated two hours after this exposure by an arbitrary scale going from0 to 3 by two observers ignorant of the treatment undergone by theanimals. The average degree of the erythema was established by groups bytaking the average of all of the observations and the anti-inflammatoryeffect was expressed in percentage of erythema remaining on the treatedanimals with reference to those of the controls having received only thedispersant. The products to be studied were administered orally one hourbefore the exposure to ultraviolet rays and the results obtained aresummarized in Table III.

The values between the parenthesis indicate the number of guinea pigstreated.

The DE of the a-monoglyceride of4-(2'-carboxyphenylamino)-7-chloro-quinoline was about 50 mg./kg. ascompared to 100 mg./kg. for4-(2.-carbomethoxyphenylamino)-7-chloro-quinoline, 50-100 mg./kg. for

aspirin and 100 mg./kg. for amodiaquinine.

As can be seen from Table IV the u-monoglyceride of4-(2-carboxyphenylamino)-7-chloro-quinoline is less toxic than4-(2'-carbomethoxyphenylamino) -7'-chloro-quinoline.

Various modifications of the compositions and process of the inventionmay be made without departing from the spirit or scope thereof and it isto be understood that the invention is intended to be limited only asdefined in the appended claims.

=We claim:

1. A compound selected from the group consisting of the oemonoglycerideof 4-(2-carboxyphenylamino)-7- chloro-quinoline and its non-toxic,pharmaceutically acceptable acid addition salts.

2. The a-monoglyceride of 4-(2'-carboxyphenylamino) 7-chloro-quinoline.

3. The hydrochloride of the a-monoglyceride of 4-(2'- carboxyphenylamino-7-chloro-quinoline.

4. A process for the preparation of the tx-monoglyceride of4-(2'-carboxyphenylamino)7-chloro-quinoline which comprises reacting ano-nitrobenzoyl halide with 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane inthe presence of an organic tertiary base to form (2,3-isopropylidenedi-0Xy)-propyl o-nitrobenzoate, catalytically hydrogenating the latter toform (2,3-isopropylidenedioxy)-propyl anthranilate, condensing thelatter with 4,7-dichloroquinoline in the presence of a mineral acid toform a salt of the a-monoglyceride of 4-(2'-carboxyphenylamino)-7-chloro-quinoline and recovering the a-monoglyceride by reaction of thesaid salt under alkaline conditions.

5. The process of claim 4 wherein the a-monoglyceride of4-(2'-carboxyphenylamino)-7-chloro-quinoline is reacted with an acidselected from the group consisting of mineral acids and organic acids toform the corresponding acid addition salt of the said a-monoglyceride.

6. The process of claim 4 wherein the tertiary organic base is pyridine.

7. The process of claim 4 wherein the catalytic hydrogenation iseffected in ethanol With a palladized carbon black catalyst.

3. A process for the preparation of the wmonoglyceride of4-(2'-carboxyphenylamino)-7-chloro-quinoline which comprises reactingo-nitrobenzoyl chloride with 2,2-dimethyl-4-hydroxymethyl-1,3-diox0lanein the presence of pyridine to form (2,3-isopropylidenedioxy)-propylo-nitro-benozate, catalytically hydrogenating the latter in etha- 1101in the presence of a palladized carbon black catalyst to form(2,3-isopropylidenedioxy)-pr0pyl anthranilate, condensing the latterwith 4,7-dichloro-quinoline in the presence of hydrochloric acid to formthe hydrochloride of the a-rnonoglyceride of4-(2'-carboxyphenyla1nino)-7- chloro-quinoline and reacting the latterwith an ammo- .8 nium solution to form the a-monoglyceride of4-(2'-carboxyphenylarnino) -7-chloro-quinoline.

References Cited by the Examiner UNITED STATES PATENTS NICHOLAS S.RIZZO, Primary Examiner.

HENRY R. J ILES, Examiner.

DONALD G. DAUS, Assistant Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE A-MONOGLYCERIDEOF 4-(2''-CARBOXYPHENYLAMINO)-7CHLORO-QUINOLINE AND ITS NON-TOXIC,PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS.
 8. A PROCESS FOR THEPREPARATION OF THE A-MONOGLYCERIDE OF4-(2''-CARBOXYPHENYLAMINO)-7-CHLORO-QUINOLINE WHICH COMPRISES REACTINGO-NITROBENZOYL CHLORIDE WITH 2,2-DIMETHYL-4-HYDROXYMETHYL-1,3-DIOXOLANEIN THE PRESENCE OF PYRIDINE TO FORM (2,3-ISOPROPYLIDENEDIOXY)-PROPYLO-NITRO-BENZOATE, CATALYTICALLY HYDROGENATING THE LATTER IN ETHANOL INTHE PRESENCE OF A PALLADIZED CARBON BLACK CATALYST TO FORM(2,3-ISOPROPYLIDENEDIOXY)-PROPYL ANTHRANILATE, CONDENSING THE LATTERWITH 4,7-DICHLORO-QUINOLINE IN THE PRESENCE OF HYDROCHLORIC ACID TO FORMTHE HYDROCHLORIDE OF THE A-MONOGLYCERIDE OF4-(2''-CARBOXYPHENYLAMINO)-7CHLORO-QUINOLINE AND REACTING THE LATTERWITH AN AMMONIUM SOLUTION TO FORM THE A-MONOGLYCERIDE OF4-(2''-CARBOXYPHENYLAMINO)-7-CHLORO-QUINOLINE.